Cocaine is a common drug of abuse among HIV-infected persons, and its use has been independently associated with poorer clinical outcomes, including more rapid HIV disease progression. In addition to indirect effects on psychosocial stability that limit adherence to medical care and HIV treatments, data also suggest direct effects of cocaine on CD4+ and CD8+ T cell function and enhanced HIV replication that may contribute to accelerated HIV disease. Cocaine has been shown to have adverse effects on cells in multiple in vitro and animal model systems- primarily through mitochondrial induction of the apoptotic pathway. Given the primary role of mitochondria-mediated apoptosis in CD4+ T cell depletion during HIV-infection, we suspect that the untoward effects of cocaine on CD4+ T cells and HIV disease progression are mediated by mitochondria- induced apoptosis, though data directly linking cocaine exposure to enhanced CD4+ T cell apoptosis are lacking. Mitochondrial DNA (mtDNA) is present in each mitochondrion, encodes protein subunits required for cellular oxidative phosphorylation, and is a primary mediator of oxidative stress, antioxidant capacity, and induction of apoptosis in response to cellular damage. Mitochondrial DNA haplogroups are based on inherited polymorphic variation, denote maternal ancestry and human migrations, and have been associated with risk of degenerative and metabolic diseases, and longevity. Our group has devoted considerable effort to understanding the relevance of mtDNA variation in HIV treatment complications, and a recent study by other investigators identified associations between haplogroups and HIV disease progression in cohorts of persons of European descent. The goals of the proposed pilot studies are to better understand interactions between drug use and altered HIV progression and AIDS pathogenesis through novel analyses of the effects of cocaine use on CD4+ T cells at both the population and mechanistic level, and how these effects are modulated by mtDNA variation. We will attain these goals through two study aims that will utilize secondary analysis of existing data and specimens: 1) To identify associations between mtDNA variation and cocaine-induced effects on CD4+ and CD8+ T cell activation and apoptosis in peripheral blood cells from HIV-infected persons;and 2) To identify associations between mtDNA variation and pre- and post-antiretroviral therapy CD4+ T cell levels in HIV-infected cocaine users and non-users. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to explore the role that variation in human mitochondrial genes may play in the more severe immune dysfunction and faster disease progression seen in HIV-infected persons who use cocaine. Results from these pilot studies will improve our understanding of the relationships between mitochondrial genes, cocaine, and the immune system, and they will inform future clinical trials designed to improve outcomes of HIV-infected persons.